Abstract
BackgroundNowadays, there is a considerable gap in knowledge concerning the mechanism(s) by which long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) interact to induce bronchodilation. This study aimed to characterise the pharmacological interaction between glycopyrronium bromide and indacaterol fumarate and to identify the mechanism(s) leading to the bronchorelaxant effect of this interaction.MethodsThe effects of glycopyrronium plus indacaterol on the contractile tone of medium and small human isolated bronchi were evaluated, and acetylcholine and cAMP concentrations were quantified. The interaction was assessed by Bliss Independence approach.ResultsGlycopyrronium plus indacaterol synergistically inhibited the bronchial tone (medium bronchi, +32.51 % ± 7.86 %; small bronchi, +28.46 % ± 5.35 %; P < 0.05 vs. additive effect). The maximal effect was reached 140 min post-administration. A significant (P < 0.05) synergistic effect was observed during 9 h post-administration on the cholinergic tone, but not on the histaminergic contractility. Co-administration of glycopyrronium and indacaterol reduced the release of acetylcholine from the epithelium but not from bronchi, and enhanced cAMP levels in bronchi and epithelial cells (P < 0.05 vs. control), an effect that was inhibited by the selective KCa++ channel blocker iberiotoxin. The role of cAMP-dependent pathway was confirmed by the synergistic effect elicited by the adenylate cyclase activator forskolin on glycopyrronium (P < 0.05 vs. additive effect), but not on indacaterol (P > 0.05 vs. additive effect), with regard of the bronchial relaxant response and cAMP increase.ConclusionsGlycopyrronium/indacaterol co-administration leads to a synergistic improvement of bronchodilation by increasing cAMP concentrations in both airway smooth muscle and bronchial epithelium, and by decreasing acetylcholine release from the epithelium.
Highlights
Nowadays, there is a considerable gap in knowledge concerning the mechanism(s) by which long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) interact to induce bronchodilation
The synergistic interaction between the LAMA aclidinium bromide and the LABA formoterol fumarate has been deeply characterised from a pharmacological point of view [6], we cannot exclude the possibility that different LABA/LAMA combinations such as glycopyrronium bromide (NVA237) plus indacaterol fumarate (QAB149) may show a different pharmacological interaction [10]
Compounds were stored in small aliquots at −80 °C until their use. Isolated segmental bronchi Both glycopyrronium and indacaterol induced potent concentration-dependent relaxation of human isolated bronchi submaximally pre-contracted with acetylcholine (−Log dose concentration inducing 50 % maximal effect [pEC50] glycopyrronium: 8.44 ± 0.02; pEC50 indacaterol: 7.39 ± 0.29); glycopyrronium was more potent than indacaterol (P < 0.05)
Summary
There is a considerable gap in knowledge concerning the mechanism(s) by which long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) interact to induce bronchodilation. Treatment for patients suffering from chronic obstructive pulmonary disease (COPD) not controlled by a single bronchodilator requires the addition of a second bronchodilator characterised by a different mechanism of action [1]. We strongly support this therapeutic approach because using multiple drugs in combination may allow lower doses of individual agents, decrease adverse effects, simplify medication regimens and improve compliance [2]. Several pathways have been proposed to clarify the intracellular cross-talk elicited by combining β2-adrenoceptor agonists and anti-muscarinic agents in ASM cells and parasympathetic neurons [9, 11], there is still a considerable gap in knowledge with regard to the pharmacological mechanism(s) by which a LABA and a LAMA interact when they induce bronchodilation
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